Processes for the preparation of benzodiazepine derivatives

ABSTRACT

The present invention relates to processes and intermediates useful in the preparation of biologically active molecules, especially in the synthesis of Respiratory Syncytial Virus (RSV) inhibitors. The present invention also relates to processes and intermediates for the preparation of compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     In particular, the present invention also relates to processes and intermediates for the preparation of compound I-a:

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/459,955 filed on Feb. 16, 2017, and U.S. Provisional Application No.62/459,953 filed on Feb. 16, 2017. The entire teachings of the aboveapplication are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to processes and intermediates useful inthe preparation of biologically active molecules, especially in thesynthesis of Respiratory Syncytial Virus (RSV) inhibitors.

BACKGROUND OF THE INVENTION

Human respiratory syncytial virus (HRSV) is a negative-sense, singlestranded, RNA paramyxovirus (K M. Empey, et al., Rev. Anti-InfectiveAgents, 2010, 50 (1 May), 1258-1267). RSV is the leading cause of acutelower respiratory tract infections (ALRI) and affects patients of allages. The symptoms in adults are usually not severe and are typicallyanalogous to a mild cold. However, in infants and toddlers the virus cancause lower respiratory tract infections including bronchiolitis orpneumonia with many of them requiring hospitalization. Nearly allchildren have been infected by age 3. There are known high-risk groupsthat infection with RSV is more likely to progress into the ALRI.Premature infants and/or infants suffering from lung or cardiac diseaseare at the highest risk to develop ALRI. Additional high-risk groupsinclude the elderly, adults with chronic heart and/or lung disease, stemcell transplant patients and the immunosuppressed.

Currently, there is no vaccine available to prevent HRSV infection.Palivizumab is a monoclonal antibody that is used prophylactically toprevent HRSV infection in high risk infants, e.g. premature infants, andinfants with cardiac and/or lung disease. The high cost of palivizumabtreatment limits its use for general purposes. Ribavirin has also beenused to treat HRSV infections, but its effectiveness is limited. Thereis a major medical need for new and effective HRSV treatments that canbe used generally by all population types and ages.

There have been several RSV fusion inhibitors that have been disclosedin the following publications: WO2010/103306, WO2012/068622,WO2013/096681, WO2014/060411, WO2013/186995, WO2013/186334,WO2013/186332, WO2012/080451, WO2012/080450, WO2012/080449,WO2012/080447, WO2012/080446, and J. Med. Chem. 2015, 58, 1630-1643.Examples of other N-protein inhibitors for treatment of HRSV have beendisclosed in the following publications: WO2004/026843, J. Med. Chem.2006, 49, 2311-2319, and J. Med. Chem. 2007, 50, 1685-1692. Examples ofL-protein inhibitors for HRSV have been disclosed in the followingpublications: WO2011/005842, WO2005/042530, Antiviral Res. 2005, 65,125-131, and Bioorg. Med. Chem. Lett. 2013, 23, 6789-6793. Examples ofnucleosides/polymerase inhibitors have been disclosed in the followingpublications: WO2013/242525 and J. Med. Chem. 2015, 58, 1862-1878.

There is a need for the development of effective treatments for HRSV.The present invention has identified compounds that are aminoheteroarylsubstituted benzodiazepines, and inhibit HRSV. The invention includesmethods to prepare the compounds as well as methods of using thesecompounds to treat disease.

SUMMARY OF THE INVENTION

The present invention provides methods for preparing compounds offormula (I), or a pharmaceutically acceptable salt thereof:

wherein {circle around (A)} is an optionally substituted aryl oroptionally substituted heteroaryl, preferably {circle around (A)} isoptionally substituted pyridyl; each n is independently selected from 1and 2; preferably each n is 1; m is 0, 1, 2, 3, or 4; preferably m is 0;R₁ is selected from the group consisting of:

1) optionally substituted —C₁-C₈ alkyl;

2) optionally substituted —C₃-C₈ cycloalkyl; and

3) optionally substituted 3- to 12-membered heterocyclic;

Alternatively, two adjacent R₁ groups are taken together with the carbonatoms to which they are attached to form a fused ring; two geminal R₁groups are taken together with the carbon atom to which they areattached to form a spiro ring; or two R₁ groups on nonadjacent carbonatoms are taken together to form a bridging group, such as —CH₂— or—CH₂CH₂—.

Preferably, when m is not 0, each R₁ is methyl.

A preferred compound of formula (I) is compound (I-a):

The invention further relates to methods for increasing product yieldand decreasing process steps for intermediate and large scale productionof compounds of formula (I), such as compound (I-a). These compounds areuseful as RSV inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

In its principal embodiment, the present invention provides a processfor the preparation of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof:

wherein {circle around (A)}, R₁, m and n are previously defined. Incertain embodiments,

is selected from the groups set forth below:

The process comprises the steps of1) reacting a compound of formula (VII),

wherein R₇ is selected from the group consisting of hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkenyl, 3- to 8-membered heterocyclic, aryl, and heteroaryl; and Xis a leaving group, such as, but not limited to, halogen or —O-triflate;with a compound of formula (VII-X),

wherein PG is hydrogen or an amine protecting group, such as, but notlimited to cbz, Boc, methoxycarbonyl, or 9-fluorenyl-methoxycarbonyl;to produce a compound of formula (VIII),

2) reacting the compound of formula (VIII) with a compound of formula(IX):

wherein R₁, m and n are as previously defined; to produce a compound offormula (X):

3) reacting the compound of formula (X) with a compound of formula(III),

wherein R₅ is selected from the group consisting of —O(CO)O—R₆,optionally substituted aryl, and optionally substituted heteroaryl; andR₆ is selected from the group consisting of optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈ alkenyl, optionally substitutedC₂-C₈ alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted C₃-C₈ cycloalkenyl, optionally substituted 3- to 8-memberedheterocyclic, optionally substituted aryl, and optionally substitutedheteroaryl;to form a compound of formula (V),

and4) reacting the compound of formula (V) with a cyclizing reagent to formthe compound of formula (I).

A preferred embodiment of a compound of formula (VIII) is a compound offormula (VIII-a), formula (VIII-b), or formula (VIII-c):

wherein R₄ is selected from halogen, methyl, CF₃, and CN. A morepreferred embodiment of a compound of formula (VIII) is a compound offormula (VIII-d),

A preferred embodiment of a compound of formula (X) is a compound offormula (X-a), formula (X-b), or formula (X-c):

A more preferred embodiment of a compound of formula (X) is a compoundof formula (X-d):

In a preferred embodiment, the compound of formula (III) is compound(III-a):

A preferred embodiment of the compound of formula (V) is compound (V-a).

The compound of formula (III) can be formed by reacting compound (IV),

with an activating agent of the formula Y—C(O)R₅, wherein Y is a leavinggroup, such as halide or 1-imidazolyl.

Compound (IV) can be prepared, for example, by resolution of a racemicmixture of compound (IV) and its enantiomer.

In one embodiment, the invention provides a compound of formula (I), ora pharmaceutically acceptable salt thereof, in an amorphous solid form.In this embodiment, the compound of Formula I is preferably compound(I-a) or a pharmaceutically acceptable salt thereof and more preferably,the compound of formula (I) is compound (I-a) free base.

In another embodiment, the invention provides compositions comprising anamorphous solid form of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable hydrophilicpolymer to enhance activity.

In one embodiment of this aspect of the invention, the hydrophilicpolymer is selected from homopolymer of N-vinyl lactam, copolymers ofN-vinyl lactam, cellulose esters, cellulose ethers, polyalkylene oxide,polyacrylate, polymethacrylate, polyacrylamide, polyvinyl alcohol, vinylacetate polymer, oligosaccharides, and polysaccharides. Non-limitingexamples of suitable hydrophilic polymers include homopolymer of N-vinylpyrrolidone, copolymers of N-vinyl pyrrolidone, copolymers of N-vinylpyrrolidone and vinyl acetate, copolymers of N-vinyl pyrrolidone andvinyl propionate, polyvinylpyrrolidone, methylcellulose, ethylcellulose,hydroxyalkylcelluloses, hydroxypropylcellulose,hydroxyalkylalkylcellulose, hydroxypropylmethylcellulose, cellulosephthalate, cellulose succinate, cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulosesuccinate, hydroxypropylmethylcellulose acetate succinate, polyethyleneoxide, polypropylene oxide, copolymer of ethylene oxide and propyleneoxide, methacrylic acid/ethyl acrylate copolymer, methacrylicacid/methyl methacrylate copolymer, butylmethacrylate/2-dimethylaminoethyl methacrylate copolymer,poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate), copolymerof vinyl acetate and crotonic acid, partially hydrolyzed polyvinylacetate, carrageenan, galactomannan, or xanthan gum.

In yet another embodiment of this aspect of the invention, thehydrophilic polymer is a homopolymer or copolymer of N-vinylpyrrolidone. Preferably, the hydrophilic polymer is copovidone.

The compositions comprising a compound of formula (I), or apharmaceutically acceptable salt in an amorphous solid form and apharmaceutically acceptable hydrophilic polymer can be prepared by avariety of techniques such as, without limitation, melt-extrusion,spray-drying, coprecipitation, freeze drying, or other solventevaporation techniques, with melt-extrusion and spray-drying beingpreferred. The melt-extrusion process typically comprises the steps ofpreparing a melt which includes the active ingredient(s), thehydrophilic polymer(s) and preferably a surfactant(s), and then coolingthe melt until it solidifies. “Melting” means a transition into a liquidor rubbery state in which it is possible for one component to becomeembedded, preferably homogeneously embedded, in the other component orcomponents. In many cases, the polymer component(s) will melt and theother components including the active ingredient(s) will dissolve in themelt thereby forming a solution. Melting usually involves heating abovethe softening point of the polymer(s). The preparation of the melt cantake place in a variety of ways. The mixing of the components can takeplace before, during or after the formation of the melt. For example,the components can be mixed first and then melted or be simultaneouslymixed and melted. The melt can also be homogenized in order to dispersethe active ingredient(s) efficiently. In addition, it may be convenientfirst to melt the polymer(s) and then to mix in and homogenize theactive ingredient(s). In one example, all materials except surfactant(s)are blended and fed into an extruder, while the surfactant(s) is moltenexternally and pumped in during extrusion.

Synthetic Schemes

The present invention will be better understood in connection withschemes 1-2, wherein {circle around (A)}, R₁, PG, X, m, n, and R₅ are aspreviously defined unless otherwise indicated.

It will be readily apparent to one of ordinary skill in the art that theprocess of the present invention can be practiced by substitution of theappropriate reactants and that the order of the steps themselves can bevaried.

A chemical route to the synthesis of the hydrazide, the compound offormula (X) is summarized in scheme 1.

R₇ is selected from the group consisting of hydrogen, C₁-C₈ alkyl, C₂-C₈alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, 3- to8-membered heterocyclic, aryl, and heteroaryl. Preferably, the compoundof formula (VII) is 3-halo-5-(trifluoromethyl)-2-pyridinecarboxylic acidor alkyl 3-halo-5-(trifluoromethyl) picolinate and more preferably ethyl3-chloro-5-(trifluoromethyl)-picolinate, which is commerciallyavailable. Preferred compounds of formula (VII-X) include hydrazinemonohydrate, Boc-hydrazine or Cbz-hydrazine.

In one embodiment, R₇ is C₁-C₈ alkyl, preferably methyl or ethyl. Inthis embodiment, the reaction of the compound of formula (VII) andhydrazine monohydrate typically takes place in a protic solvent such as,but not limited to, methanol, ethanol, or isopropyl alcohol or a mixtureof two or more thereof. The reaction temperature is typically about 10°C. to about 70° C. and the reaction time is typically about 3 to 12hours.

In another embodiment, R₇ is hydrogen, and the compound of formula (VII)is converted to the compound of formula (VIII) by coupling with acompound of formula (VII-X) in the presence of an amide coupling agentsuch as 1,1′-carbonyldiimidazole, bis(2-oxo-3-oxazolidinyl)-phosphinicchloride, 1-hydroxy-7-azabenzotriazole, 1-hydroxybenzotriazole hydrate,3-hydroxy-1,2,3-benzotriazin-4(3H)-one,1-(3-dimethyaminopropyl)-3-ethylcarbodiinide hydrochloride,4-nitrophenol, pentafluorophenol, 2-hydroxypyridine,N-hydroxysuccinimide, N-hydroxyphthalamide, 2-mercaptobenzoxazole,trimethylacetyl chloride, isobutylchloroformate,chlorodimethoxytriazole, oxalyl chloride, 2-hydroxypyridine-N-oxide,5-nitro-2-hydroxypyridine, Boc-L-valine anhydride, or mixtures thereof.Examples of suitable solvents for this reaction include, but are notlimited to, isopropyl acetate, ethyl acetate, dichloromethane, acetone,THF, NMP, 2-methyltetrahydrofuran, and acetonitrile. Particular reactionconditions will vary depending on the nature of the coupling reagent andwill be known to those of ordinary still in the art.

A compound of formula (VIII) can be transformed to a compound of formula(X) by amination with a compound of formula (IX), The compound offormula (IX) can be, but is not limited to, morpholine,2-methylmorpholine and its stereoisomers, 3-methylmorpholine and itsstereoisomers, 3,5-dimethylmorphine and its stereoisomers,2,6-dimethylmorphine and its stereoisomers,3-oxa-8-azabicyclo[3.2.1]octane, 2-oxa-5-azabicyclo[2.2.1]heptane,8-oxa-3-azabicyclo[3.2.1]octane. The reaction typically takes place asneat or in an aprotic solvent, such as, but not limited to toluene, THFor dichloromethane. The reaction temperature is typically about 10° C.to about 100° C. and the reaction time is typically 3 to 12 hours.

In one embodiment, wherein PG is not hydrogen, the compound of formula(X) is deprotected by removing PG. Suitable deprotection conditionsdepend on the identity of PG and are known to those skilled in the art,for example, as described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999).

Scheme 2 illustrates the synthesis of the compound of formula (I),

The compound (XI) is either commercially available or can be synthesizedby methods known to those of ordinary skill in the art. The chiralseparation of the racemic compound (XI) can be performed using methodssuch as, but not limited to, treatment with a chiral acid and separationof the diastereoisomeric salt by crystallization or chromatography,capillary electrophoresis (CE), supercritical fluid chromatography(SFC), capillary electrochromatography (CEC), gas chromatography (GC),high performance liquid chromatography (HPLC), and crystallization withchiral salts, then following separation of diasteromeric analogs toprovide a chiral compound (IV), S-isomer. In one embodiment, compound(IV) is produced from racemic compound (XI) using the method disclosedin U.S. Provisional Application No. 62/585,192.

In one embodiment, SFC is used to obtain chiral compound (IV), themobile phase is carbon dioxide (CO₂) or a mixture of carbon dioxide anda polar organic co-solvent such as, but not limited to, methanol,ethanol, or 2-propanol; the temperature range is limited from 5 to40-50° C., preferably, the temperature is room temperature (about 25°C.). The procedures and conditions of SFC will vary and depend on thenature of racemic compounds and will be known to those ordinary skillsin the art.

In one aspect, chiral compound (IV) is obtained with greater than about90% enantiomeric excess purity (ee) after SFC separation. In one aspect,chiral compound (IV) is obtained with greater than about 95%enantiomeric excess purity (ee) after SFC separation. In one aspect,chiral compound (IV) is obtained with greater than about 98%enantiomeric excess purity (ee) after SFC separation.

In one embodiment, after chiral separation, besides chiral compound(IV), another epimer, chiral compound (IV-A), R-isomer, is alsoobtained:

In one embodiment, the chiral compound (IV-A), is racemized under basicconditions to obtain racemic compound (XI). The racemization takes placein a protic solvent, such as, but not limited to, methanol, ethanol,^(t)BuOH or isopropyl alcohol, in the presence of a base, such as, butnot limited to NaOMe or ^(t)BuOK. The reaction temperature is typicallyabout 10° C. to about 70° C. and the reaction time is typically about 3to 24 hours.

In one embodiment, the chiral compound (IV) is transformed to a compoundof formula (III) by reaction with an amine activation agent, such as,but not limited to, 1,1′-carbonyldiimidazole, nitrophenyl chloroformate,triphosgene or phosgene. This process is typically carried out in aprotic or aprotic solvent such as, but not limited to, acetonitrile,THF, DMSO, or dichloromethane. The typical reaction temperature is about0° C. to 30° C. and the reaction time is typically about 6 to 15 hours.In one aspect, the molar ratio of compound (IV) and amine activationagent is about 1 to 1. In one aspect, the molar ratio of compound (IV)and the amine activation agent is about 1 to 2. In one aspect, the molarratio of the chiral compound (IV) and the amine activation agent isabout 1 to 3. Preferably, the molar ratio of the chiral compound (IV)and the amine activation agent is about 1 to 3.

In one embodiment, PG is hydrogen, the reaction of the compound offormula (III) with the compound of formula (X) is carried out in aprotic solvent such as, but not limited to, acetonitrile, THF, DMSO,DMF, sulfolane or 1-methyl-2-pyrrolidone. The typical reactiontemperature is about 10 to 50° C. and the reaction time is typically 6to 48 hours. The reaction is typically conducted at a concentration ofthe compound of formula (III) about 1 M to 3 M, preferably theconcentration of the compound of formula (III) is 1.5M. The molar ratioof the compound of formula (III) and the compound of formula (X) is 1:1.

The compound of formula (V) can be cyclized to a compound of formula (I)by reaction with a cyclizing agent, such as, but not limited to,p-toluenesulfonyl chloride, thionyl chloride, phosphorous oxychloride orHATU in the presence of an organic base. Suitable organic bases include,but are not limited to, triethylamine and diisopropylethylamine. Thisprocess is carried out in an aprotic solvent, such as, but not limitedto, acetonitrile, THF, DMF, DMSO, NMP, acetone, dichloromethane, ethylacetate or isopropyl acetate. The reaction temperature is about 0° C. toabout 30° C., and the reaction time is typically 3 to 15 hours.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “aryl,” as used herein, refers to a mono- or polycycliccarbocyclic ring system comprising at least one aromatic ring,including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl,indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system thatcomprises at least one aromatic ring. Polycyclic aryls can comprisefused rings, covalently attached rings or a combination thereof.

The term “heteroaryl,” as used herein, refers to a mono- or polycyclicaromatic radical having one or more ring atom selected from S, O and N;and the remaining ring atoms are carbon, wherein any N or S containedwithin the ring may be optionally oxidized. Heteroaryl includes, but isnot limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl,thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzoxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fusedrings, covalently attached rings or a combination thereof.

In accordance with the invention, aromatic groups can be substituted orunsubstituted.

The term “bicyclic aryl” or “bicyclic heteroaryl” refers to a ringsystem consisting of two rings wherein at least one ring is aromatic;and the two rings can be fused or covalently attached.

The term “alkyl” as used herein, refers to saturated, straight- orbranched-chain hydrocarbon radicals. “C₁-C₄ alkyl,” “C₁-C₆ alkyl,”“C₁-C₈ alkyl,” “C₁-C₁₂ alkyl,” “C₂-C₄ alkyl,” or “C₃-C₆ alkyl,” refer toalkyl groups containing from one to four, one to six, one to eight, oneto twelve, 2 to 4 and 3 to 6 carbon atoms respectively. Examples ofC₁-C₈ alkyl radicals include, but are not limited to, methyl, ethyl,propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl andoctyl radicals.

The term “alkenyl” as used herein, refers to straight- or branched-chainhydrocarbon radicals having at least one carbon-carbon double bond bythe removal of a single hydrogen atom. “C₂-C₈ alkenyl,” “C₂-C₁₂alkenyl,” “C₂-C₄ alkenyl,” “C₃-C₄ alkenyl,” or “C₃-C₆ alkenyl,” refer toalkenyl groups containing from two to eight, two to twelve, two to four,three to four or three to six carbon atoms respectively. Alkenyl groupsinclude, but are not limited to, for example, ethenyl, propenyl,butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and the like.

The term “alkynyl” as used herein, refers to straight- or branched-chainhydrocarbon radicals having at least one carbon-carbon double bond bythe removal of a single hydrogen atom. “C₂-C₈ alkynyl,” “C₂-C₁₂alkynyl,” “C₂-C₄ alkynyl,” “C₃-C₄ alkynyl,” or “C₃-C₆ alkynyl,” refer toalkynyl groups containing from two to eight, two to twelve, two to four,three to four or three to six carbon atoms respectively. Representativealkynyl groups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, heptynyl, octynyl, and the like.

The term “cycloalkyl”, as used herein, refers to a monocyclic orpolycyclic saturated carbocyclic ring or a bi- or tri-cyclic groupfused, bridged or spiro system, and the carbon atoms may be optionallyoxo-substituted or optionally substituted with exocyclic olefinic doublebond. Preferred cycloalkyl groups include C₃-C₁₂ cycloalkyl, C₃-C₆cycloalkyl, C₃-C₈ cycloalkyl and C₄-C₇ cycloalkyl. Examples of C₃-C₁₂cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl,4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl,spiro[2.5]octyl, 3-methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, andthe like.

The term “cycloalkenyl”, as used herein, refers to monocyclic orpolycyclic carbocyclic ring or a bi- or tri-cyclic group fused, bridgedor spiro system having at least one carbon-carbon double bond and thecarbon atoms may be optionally oxo-substituted or optionally substitutedwith an exocyclic olefinic double bond. Preferred cycloalkenyl groupsinclude C₃-C₁₂ cycloalkenyl, C₃-C₈ cycloalkenyl or C₅-C₇ cycloalkenylgroups. Examples of C₃-C₁₂ cycloalkenyl include, but not limited to,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl,spiro[2.5]oct-4-enyl, spiro[4.4]non-1-enyl, bicyclo[4.2.1]non-3-en-9-yl,and the like.

As used herein, the term “arylalkyl” means a functional group wherein analkylene chain is attached to an aryl group, e.g., —CH₂CH₂-phenyl. Theterm “substituted arylalkyl” means an arylalkyl functional group inwhich the aryl group is substituted. Similarly, the term“heteroarylalkyl” means a functional group wherein an alkylene chain isattached to a heteroaryl group. The term “substituted heteroarylalkyl”means a heteroarylalkyl functional group in which the heteroaryl groupis substituted.

As used herein, the term “alkoxy” employed alone or in combination withother terms means, unless otherwise stated, an alkyl group having thedesignated number of carbon atoms connected to the rest of the moleculevia an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy,2-propoxy (isopropoxy) and the higher homologs and isomers. Preferredalkoxy are (C₁-C₃) alkoxy.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclic and cycloalkenyl moiety described herein can also be analiphatic group or an alicyclic group.

An “aliphatic” group is a non-aromatic moiety comprised of anycombination of carbon atoms, hydrogen atoms, halogen atoms, oxygen,nitrogen or other atoms, and optionally contains one or more units ofunsaturation, e.g., double and/or triple bonds. Examples of aliphaticgroups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH,NH, NH₂, C(O), S(O)₂, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH₂, S(O)₂NH,S(O)₂NH₂, NHC(O)NH₂, NHC(O)C(O)NH, NHS(O)₂NH, NHS(O)₂NH₂, C(O)NHS(O)₂,C(O)NHS(O)₂NH or C(O)NHS(O)₂NH₂, and the like, groups comprising one ormore functional groups, non-aromatic hydrocarbons (optionallysubstituted), and groups wherein one or more carbons of a non-aromatichydrocarbon (optionally substituted) is replaced by a functional group.Carbon atoms of an aliphatic group can be optionally oxo-substituted. Analiphatic group may be straight chained, branched, cyclic, or acombination thereof and preferably contains between about 1 and about 24carbon atoms, more typically between about 1 and about 12 carbon atoms.In addition to aliphatic hydrocarbon groups, as used herein, aliphaticgroups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls,such as polyalkylene glycols, polyamines, and polyimines, for example.Aliphatic groups may be optionally substituted.

The terms “heterocyclic” or “heterocycloalkyl” can be usedinterchangeably and referred to a non-aromatic ring or a bi- ortri-cyclic group fused, bridged or spiro system, where (i) each ringsystem contains at least one heteroatom independently selected fromoxygen, sulfur and nitrogen, (ii) each ring system can be saturated orunsaturated (iii) the nitrogen and sulfur heteroatoms may optionally beoxidized, (iv) the nitrogen heteroatom may optionally be quaternized,(v) any of the above rings may be fused to an aromatic ring, and (vi)the remaining ring atoms are carbon atoms which may be optionallyoxo-substituted or optionally substituted with exocyclic olefinic doublebond. Representative heterocycloalkyl groups include, but are notlimited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl,quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl,8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl,1-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl.Such heterocyclic groups may be further substituted. Heteroaryl orheterocyclic groups can be C-attached or N-attached (where possible).

It is understood that any alkyl, alkenyl, alkynyl, alicyclic,cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphaticmoiety or the like, described herein can also be a divalent ormultivalent group when used as a linkage to connect two or more groupsor substituents, which can be at the same or different atom(s). One ofskill in the art can readily determine the valence of any such groupfrom the context in which it occurs.

The term “substituted” refers to substitution by independent replacementof one, two, or three or more of the hydrogen atoms with substituentsincluding, but not limited to, —F, —Cl, —Br, —I, —OH, C₁-C₁₂-alkyl;C₂-C₁₂-alkenyl, C₂-C₁₂-alkynyl, —C₃-C₁₂-cycloalkyl, protected hydroxy,—NO₂, —N₃, —CN, —NH₂, protected amino, oxo, thioxo, —NH—C₂-C₈-alkenyl,—NH—C₂-C₈-alkynyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl, —NH— heteroaryl,—NH-heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino,—O—C₁-C₁₂-alkyl, —O—C₂-C₈-alkenyl, —O—C₂-C₈-alkynyl,—O—C₃-C₁₂-cycloalkyl, —O-aryl, —O-heteroaryl, —O-heterocycloalkyl,—C(O)—C₁-C₁₂-alkyl, —C(O)—C₂-C₈-alkenyl, —C(O)—C₂-C₈-alkynyl,—C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH—C₂-C₈-alkenyl,—CONH—C₂-C₈-alkynyl, —CONH—C₃-C₁₂-cycloalkyl, —CONH-aryl,—CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl,—OCO₂—C₂-C₈-alkenyl, —OCO₂—C₂-C₈-alkynyl, —OCO₂—C₃-C₁₂-cycloalkyl,—OCO₂-aryl, —OCO₂-heteroaryl, —OCO₂-heterocycloalkyl, —CO₂—C₁-C₁₂ alkyl,—CO₂—C₂-C₈ alkenyl, —CO₂—C₂-C₈ alkynyl, CO₂—C₃-C₁₂-cycloalkyl,—CO₂-aryl, CO₂-heteroaryl, CO₂-heterocyloalkyl, —OCONH₂,—OCONH—C₁-C₁₂-alkyl, —OCONH—C₂-C₈-alkenyl, —OCONH—C₂-C₈-alkynyl,—OCONH—C₃-C₁₂-cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl,—OCONH-heterocyclo-alkyl, —NHC(O)H, —NHC(O)—C₁-C₁₂-alkyl,—NHC(O)—C₂-C₈-alkenyl, —NHC(O)—C₂-C₈-alkynyl, —NHC(O)—C₃-C₁₂-cycloalkyl,—NHC(O)-aryl, —NHC(O)— heteroaryl, —NHC(O)-heterocyclo-alkyl,—NHCO₂—C₁-C₁₂-alkyl, —NHCO₂—C₂-C₈-alkenyl, —NHCO₂— C₂-C₈-alkynyl,—NHCO₂—C₃-C₁₂-cycloalkyl, —NHCO₂-aryl, —NHCO₂-heteroaryl,—NHCO₂-heterocycloalkyl, —NHC(O)NH₂, —NHC(O)NH—C₁-C₁₂-alkyl,—NHC(O)NH—C₂-C₈-alkenyl, —NHC(O)NH—C₂-C₈-alkynyl,—NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl,—NHC(O)NH-heterocycloalkyl, NHC(S)NH₂, —NHC(S)NH—C₁-C₁₂-alkyl,—NHC(S)NH—C₂-C₈-alkenyl, —NHC(S)NH—C₂-C₈-alkynyl,—NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl,—NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂, —NHC(NH)NH—C₁-C₁₂-alkyl,—NHC(NH)NH—C₂-C₈-alkenyl, —NHC(NH)NH—C₂-C₈-alkynyl,—NHC(NH)NH—C₃-C₁₂-cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl,—NHC(NH)NH-heterocycloalkyl, —NHC(NH)—C₁-C₁₂-alkyl,—NHC(NH)—C₂-C₈-alkenyl, —NHC(NH)—C₂-C₈-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₈-alkenyl, —C(NH)NH—C₂-C₈-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₈-alkenyl,—S(O)—C₂-C₈-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl, —SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₈-alkenyl, —SO₂NH— C₂-C₈-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁-C₁₂-alkyl, —NHSO₂—C₂-C₈-alkenyl, —NHSO₂—C₂-C₈-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₈-alkenyl, —S—C₂-C₈-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl, ormethylthio-methyl. It is understood that the aryls, heteroaryls, alkyls,cycloalkyls and the like can be further substituted.

The term “halo” or halogen” alone or as part of another substituent, asused herein, refers to a fluorine, chlorine, bromine, or iodine atom.

The term “optionally substituted”, as used herein, means that thereferenced group may be substituted or unsubstituted. In one embodiment,the referenced group is optionally substituted with zero substituents,i.e., the referenced group is unsubstituted. In another embodiment, thereferenced group is optionally substituted with one or more additionalgroup(s) individually and independently selected from groups describedherein.

The term “hydrogen” includes hydrogen and deuterium. In addition, therecitation of an atom includes other isotopes of that atom so long asthe resulting compound is pharmaceutically acceptable.

The term “hydroxy activating group,” as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxyl groupso that it will depart during synthetic procedures such as in asubstitution or an elimination reaction. Examples of hydroxyl activatinggroup include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxyl,” as used herein, refers to a hydroxy groupactivated with a hydroxyl activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxyl groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theart are described generally in T. H. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxyl protecting groups includebenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxy-carbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl,chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl,methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, allyl,benzyl, triphenyl-methyl (trityl), methoxymethyl, methylthiomethyl,benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl,trimethylsilyl, triisopropylsilyl, and the like.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups,for example.

The term “hydroxy prodrug group,” as used herein, refers to a promoietygroup which is known in the art to change the physicochemical, and hencethe biological properties of a parent drug in a transient manner bycovering or masking the hydroxy group. After said syntheticprocedure(s), the hydroxy prodrug group as described herein must becapable of reverting back to hydroxy group in vivo. Hydroxy prodruggroups as known in the art are described generally in Kenneth B. Sloan,Prodrugs, Topical and Ocular Drug Delivery, (Drugs and thePharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York(1992).

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the artare described generally in T. H. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York(1999). Examples of amino protecting groups include, but are not limitedto, methoxycarbonyl, t-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl,benzyloxycarbonyl, and the like.

The term “protected amino,” as used herein, refers to an amino groupprotected with an amino protecting group as defined above.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include chloro, bromo and iodogroups; sulfonic ester groups, such as mesylate, tosylate, brosylate,nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such compounds are well known to those skilledin the art, and it will be obvious to those skilled in the art thatindividual solvents or mixtures thereof may be preferred for specificcompounds and reaction conditions, depending upon such factors as thesolubility of reagents, reactivity of reagents and preferred temperatureranges, for example. Further discussions of aprotic solvents may befound in organic chemistry textbooks or in specialized monographs, forexample: Organic Solvents Physical Properties and Methods ofPurification, 4th ed., edited by John A. Riddick et al., Vol. II, in theTechniques of Chemistry Series, John Wiley & Sons, N Y, 1986.

The term “protic solvent,” as used herein, refers to a solvent thattends to provide protons, such as an alcohol, for example, methanol,ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Suchsolvents are well known to those skilled in the art, and it will beobvious to those skilled in the art that individual solvents or mixturesthereof may be preferred for specific compounds and reaction conditions,depending upon such factors as the solubility of reagents, reactivity ofreagents and preferred temperature ranges, for example. Furtherdiscussions of protogenic solvents may be found in organic chemistrytextbooks or in specialized monographs, for example: Organic SolventsPhysical Properties and Methods of Purification, 4th ed., edited by JohnA. Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, N Y, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable,” as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. As can beappreciated by the skilled artisan, further methods of synthesizing thecompounds of the formula herein will be evident to those of ordinaryskill in the art. Additionally, the various synthetic steps may beperformed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, 2^(nd) Ed. Wiley-VCH (1999); T. W. Greene and P. G. M.Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley andSons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The term “subject,” as used herein, refers to an animal. Preferably, theanimal is a mammal. More preferably, the mammal is a human. A subjectalso refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriatefunctionalities to enhance selective biological properties. Suchmodifications are known in the art and may include those which increasebiological penetration into a given biological system (e.g., blood,lymphatic system, central nervous system), increase oral availability,increase solubility to allow administration by injection, altermetabolism and alter rate of excretion.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds, otherunsaturation, or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that the compounds include both Eand Z geometric isomers or cis- and trans-isomers. Likewise, alltautomeric forms are also intended to be included. Tautomers may be incyclic or acyclic. The configuration of any carbon-carbon double bondappearing herein is selected for convenience only and is not intended todesignate a particular configuration unless the text so states; thus, acarbon-carbon double bond or carbon-heteroatom double bond depictedarbitrarily herein as trans may be cis, trans, or a mixture of the twoin any proportion.

Certain compounds of the present invention may also exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present invention includes each conformationalisomer of these compounds and mixtures thereof.

As used herein, the term “pharmaceutically acceptable salt,” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, nontoxic acid addition salts are saltsof an amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, maleic acid, tartaric acid,citric acid, succinic acid or malonic acid or by using other methodsused in the art such as ion exchange. Other pharmaceutically acceptablesalts include, but are not limited to, adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentane-propionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Representative alkali or alkaline earth metal saltsinclude sodium, lithium, potassium, calcium, magnesium, and the like.Further pharmaceutically acceptable salts include, when appropriate,nontoxic ammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include, but are not limited to, formates,acetates, propionates, butyrates, acrylates and ethyl succinates.

Suitable concentrations of reactants used in the synthesis processes ofthe invention are 0.01M to 10M, typically 0.1M to 1M. Suitabletemperatures include −10° C. to 250° C., typically −78° C. to 150° C.,more typically −78° C. to 100° C., still more typically 0° C. to 100° C.Reaction vessels are preferably made of any material which does notsubstantial interfere with the reaction. Examples include glass,plastic, and metal. The pressure of the reaction can advantageously beoperated at atmospheric pressure. The atmospheres include, for example,air, for oxygen and water insensitive reactions, or nitrogen or argon,for oxygen or water sensitive reactions.

The term “in situ,” as used herein, refers to use of an intermediate inthe solvent or solvents in which the intermediate was prepared withoutremoval of the solvent.

Abbreviations

Abbreviations which may be used in the descriptions of the scheme andthe examples that follow are:

Ac for acetyl;AcOH for acetic acid;Boc₂O for di-tert-butyl-dicarbonate;Boc for t-butoxycarbonyl;Bz for benzoyl;Bn for benzyl;Brine for sodium chloride solution in water;t-BuOH for tert-butanol;t-BuOK for potassium tert-butoxide;Bu₄NBr for tetrabutylammonium bromide;Cbz for carbobenzyloxy;CDI for 1,1′-carbonyldiimidazole;CH₂C₁₂ for dichloromethane;CH₃ for methyl;CH₃CN for acetonitrile;Cs₂CO₃ for cesium carbonate;DIBAL-H for diisobutylaluminium hydride;DIPEA or (i-Pr)₂EtN for N,N-diisopropylethylamine;DMAP for 4-dimethylamino-pyridine;DME for 1,2-dimethoxyethane;

DMF for N,N-dimethylformamide;

DMSO for dimethyl sulfoxide;EDC for N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide;EDC.HCl for N-(3-dimethylamino-propyl)-N′-ethylcarbodiimidehydrochloride; EtOAc for ethyl acetate;EtOH for ethanol;Et₂O for diethyl ether;HATU for O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate;HCl for hydrogen chloride;K₂CO₃ for potassium carbonate;MeOH for methanol;MTBE for methyl tert-butyl ether;NaCl for sodium chloride;NaH for sodium hydride;NaHCO₃ for sodium bicarbonate or sodium hydrogen carbonate;Na₂CO₃ sodium carbonate;NaOH for sodium hydroxide;NaOMe for sodium methoxide;Na₂SO₄ for sodium sulfate;Na₂S₂O₃ for sodium thiosulfate;NH₄HCO₃ for ammonium bicarbonate;NH₄Cl for ammonium chloride;NMP for N-Methyl-2-pyrrolidoneo/n for overnight;OH for hydroxyl;Pd for palladium;PDC for pyridinium dichromate;i-PrOAc for isopropyl acetate;Ph for phenyl;PMB for p-methoxybenzyl;rt for room temperature;TBS for tert-butyl dimethylsilyl;TEA or Et₃N for triethylamine;THF for tetrahydrofuran;TPP or PPh₃ for triphenylphosphine;Ts for tosyl or —SO₂—C₆H₄CH₃;TsOH for p-tolylsulfonic acid;TMS for trimethylsilyl;TMSCl for trimethylsilyl chloride.

All other abbreviations used herein, which are not specificallydelineated above, shall be accorded the meaning which one of ordinaryskill in the art would attach.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not limiting of the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1. Preparation of3-morpholino-5-(trifluoromethyl)picolinohydrazide Step 1. Synthesis of3-Chloro-5-(trifluoromethyl)picolinohydrazide

Into a 50-L 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of ethyl3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate (4.0 kg, 15.81 mol,1.00 equiv) in ethanol (12 L) and treated with hydrazine monohydrate(1.98 kg, 2.00 equiv). The resulting solution was stirred for 2 h at 20°C. in a water bath. The resulting solution was quenched to 24 L of icewater, stirred for 30 min. The solids were filtered out. The resultingsolution was extracted with 7×8.5 L of MTBE (7×8.8 L) and the organiclayers combined, dried over sodium sulfate, filtered and concentratedunder vacuum to afford the title compound (3.65 kg) as a yellow solid.LC-MS(ESI, m/z): 240.0 [M+H]⁺.

Step 2. Synthesis of 3-morpholino-5-(trifluoromethyl)picolinohydrazide

Into a 50-L 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of3-chloro-5-(trifluoromethyl)pyridine-2-carbohydrazide (3.5 kg, 14.61mol, 1.00 equiv) in toluene (17.5 L), morpholine (6.38 kg, 73.22 mol,5.00 equiv). The resulting solution was stirred for 18 h at 96° C. in anoil bath. The reaction mixture was cooled to 25° C. with a water bath.The solid was collected by filtration. The resulting mixture wasconcentrated under vacuum. The combined solid was washed withtetrahydrofuran (9×4.5 L). The solid was filtered out. The filtrate wasconcentrated under vacuum. The residue was slurried with MTBE (10 L) andstirred for 2 hrs. The solid collected by filtration. This reaction wasrepeated with another amount of 3 kg of SM under the same conditions andthe same procedure. The crude of two batches was combined, washed withMTBE (4 L) and dried under vacuum to give the title compound (6.1 kg) asa light yellow solid. LC-MS (ES, m/z): 291.0 [MS+H⁺]. ¹H-NMR (300 MHz,DMSO-d₆): δ 9.63 (s, 1H), 8.49 (s, 1H), 7.71 (s, 1H), 4.54 (m, 2H),3.77-3.68 (m, 4H), 3.18-3.06 (m, 4H).

Example 2. Preparation of(S)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one (Compound (I-a)) Step 1: SFC Chiral Separation of3-Amino-5-phenyl-1,3-dihydro-2H benzo[e] [1,4]-diazepin-2-one

3-Amino-5-phenyl-1,3-dihydro-2H-benzo[e] [1,4]-diazepin-2-one (13.0 kg)was separated by SFC [Instrument: Waters 200 preparative SFC], Column:Chiral Pak AD, 250×50 mm I.D., 10 μm. Mobile phase: A for CO₂ and B for2-propanol (0.1% NH₃H₂O), Gradient: B 45% Flow rate: 180 mL/min]. Thefirst fraction ((R)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one, 5.0 kg, 38.5% yield) was collected as a lightyellow solid. The second fraction((S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e] [1,4]-diazepin-2-one, wasconcentrated under reduced pressure, dried under high vacuum to affordthe title compound (5.13 kg, 39.5% yield) as a light yellow solid. ¹HNMR: (DMSO-d₆ 400 MHz): δ 10.68 (br, 1H), 7.60-7.56 (m, 1H), 7.48-7.40(m, 5H), 7.27-7.24 (m, 2H), 7.21-7.17 (m, 1H), 4.24 (s, 1H). HPLCpurity: 100%; Chiral purity: 99.94% ee. LC-MS(ESI, m/z): 252.0 [M+H]⁺.

Step 2: Racemization of (R)-3-Amino-5-phenyl-1,3-dihydro-2H benzo[e][1,4]-diazepin-2-one to 3-amino-5-phenyl-1,3-dihydro-2H benzo[e][1,4]-diazepin-2-one

The first fraction ((R)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one) was racemized and used for SFC separation asfollowing: (R)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one (1.0 kg) in MeOH (10 L) was treated with NaOMe (171g) and heated at 60° C. for 16 hrs. After cooled to 25° C., theresulting mixture was quenched by addition ice-water (10 L) at 25° C.and concentrated under pressure to remove most of MeOH giving aprecipitate. The residue was triturated with additional 5 L water andfiltrated and dried under vacuum to afford racemic3-amino-5-phenyl-1,3-dihydro-2H benzo[e] [1,4]-diazepin-2-one (0.9 kg)as a pale yellow solid. ¹H NMR: (DMSO-d₆ 400 MHz): δ 10.66 (br, 1H),7.58-7.54 (m, 1H), 7.46-7.38 (m, 5H), 7.25-7.22 (m, 2H), 7.19-7.15 (m,1H), 4.22 (s, 1H). HPLC Purity: 99.7%; LC-MS(ESI, m/z): 252.2 [M+H]⁺.

The racemic amine obtained above was separated again by usingpreparative SFC.

Step 3. Preparation of(S)—N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)-1H-imidazole-1-carboxamide

1,1′-carbonyldiimidazole (1.65 kg, 3.0 eq.) was added in a reactorfilled with MeCN (12.7 L) at 20±5° C., stirred for 15 min and cooled to0±3° C. (S)-3-amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one (0.85 kg, 1.0 eq.) in batches maintaining below 5°C. during addition. The reaction was stirred at 2±3° C. for 2 hrs. andwarmed to 20±5° C. and stirred for 6 hrs. Then, the reaction was cooledto 0±3° C., treated with purified water (365.5 g, 6.0 eq.) in MeCNsolution (4.25 L) below 8° C. within 1.5 h and warmed to 20° C. Thesolid was filtered and washed with (1.7 L, 2 V) twice. The collectedsolid was dried in vacuum oven at <25° C. to afford the title compound(1.16 kg, 98.6% purity by HPLC) as a white solid. LC-MS(ESI, m/z):278.10, 346.13 [M+H]⁺.

Step 4:(S)-2-(3-morpholino-5-(trifluoromethyl)picolinoyl)-N-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)hydrazine-1-carboxamide

3-Morpholino-5-(trifluoromethyl)picolinohydrazide (0.84 kg, 1.0 eq.) wasadded into 5 L-flask filled with NMP (2 L) at 25±5° C. and stirred for10 min.

(S)—N-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)-1H-imidazole-1-carboxamide(1.0 kg, 1.0 eq.) was added to the reaction in batches at 25±5° C. andheated at 45° C. for 10 hrs. The reaction mixture was cooled to 15° C.,poured into ice-water (15 L, 3° C.) in 20 L flask, stirred for 30 min,filtered and washed with purified water (2×3 L). The collected cake wasstirred with purified water (10 L) at 25±5° C. for 1 hr, filtered andwashed with purified water (2×3 L). The collected cake was dried undervacuum oven at 27° C. for 40 h to give the crude (1.640 kg). The crude(1.64 kg) was dissolved in DCM (10 L), stirred for 30 min, charged withactive carbon (0.15 kg) and stirred for 30 min, filtered throughdiatomite (1 wt/wt), washed with DCM (2×2.5 L). The filtrate was chargedwith n-heptane (30 L) in SOL round-bottomed flask at 25±5° C. andstirred for 1 hr. The solid was filtered and wash the cake withn-heptane (2×2 L), dried under vacuum oven at 27° C. for 30 hrs to givethe title compound (1.43 kg, 95.3% purity by HPLC) as a light-yellowsolid. LC-MS(ESI, m/z): 568.19 [M+H]⁺.

Step 5:(S)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one

To a mixture of(S)-2-(3-morpholino-5-(trifluoromethyl)picolinoyl)-N-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)hydrazine-1-carboxamide(1.4 kg, 1 eq.) in DCM (11.2 L) in a flask was charged with 4 Å-MS (1.4kg) and stirred at 20±5° C. for 2 hrs. Then, it was cooled to 0° C.,charged with triethylamine (0.62 Kg, 2.5 eq.) and stirred for 10 min.p-Toluenesulfonyl chloride (0.7 kg, 1.5 eq.) in DCM (1.4 L) solution wasdropwise added to the reaction mixture with maintaining below 5° C. andstirred at 0±5° C. for 5 hrs. The reaction mixture was filtered andwashed with DCM (2×4.2 L). The filtrate was treated with water (4.2 L)at 0° C. and stirred between 0 and 10° C. for 5 min. After separation,the organic phase was washed with 5% aqueous NaHCO₃ solution (7 L),water (7 L) and brine (7 L) successively and separated. The DCM layerwas concentrated in vacuo at below 30° C. to leave ˜7 L of organiclayer. MTBE (7 L) was added to organic layer and concentrated in vacuoto leave ˜7 L of organic layer (This step was repeated once). Theorganic layer was charged with water (7 L) and stirred at 20±5° C. for 4hrs. The solid was filtered and washed with MTBE (3×2.1 L) and purifiedwater (2.8 L). The wet cake was stirred with ethyl acetate (7 L) for 12hrs, charged with n-heptane (14 L) and stirred at 20±5° C. for 5 hrs.The solid was filtered, washed with n-heptane (2×2.8 L) and dried undervacuum at ambient temperature to provide the title compound (0.776 kg,99.6% purity by HPLC, 97.8% chiral purity by chiral HPLC) as a paleyellowish solid. LC-MS(ESI, m/z): 550.17 [M+H]⁺;

¹H NMR: (DMSO-d₆ 400 MHz): δ 10.98 (br-s, 1H), 9.40 (d, J=8.0 Hz, 1H),8.69 (br-d, J=4.0 Hz, 1H), 7.89 (d, J=4.0 Hz, 1H), 7.68 (dt, J=8.0 and4.0 Hz, 1H), 7.56-7.51 (m, 3H), 7.49-7.45 (m, 2H), 7.38-7.35 (m, 2H),7.29 (br-t, J=8.0 Hz, 1H) 5.22 (d, J=8.0 Hz, 1H), 3.75-3.72 (m, 4H),3.09-3.07 (m, 4H); ¹³C (DMSO-d₆, 100 MHz): δ 167.3, 167.0, 162.8, 156.4,147.2, 139.2, 138.7, 138.4, 138.3, 138.0, 132.30, 130.7, 130.5, 129.5,128.4, 126.2, 124.5, 123.4, 121.5, 71.8, 65.9, 51.0.

Example 3. Preparation of an Amorphous Form of(S)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one

(S)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one (60.0 g) was dissolved in acetic acid (170 mL),stirred for 10 min, filtered through a fritted funnel into 3 L-flask andlyophilized. It was dried further on vacuum pump at room temperature for3 days. It was ground in a mortar and dried on vacuum with N₂ flow for 3days to provide an amorphous form of(S)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one as a yellowish solid.

Example 4. Preparation of a Complex of Amorphous Compound (I-a)[(S)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one] with copovidone

A mixture of(S)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one (6.4 g) and copovidone(poly(l-vinylpyrrolidone-co-vinyl acetate), 1.6 g) were dissolved inacetone (160 mL). The solution was concentrated in vacuo and furtherdried under high vacuum pump for 2 days. The resulting solid was groundwith a mortar and pestle and further dried in a vacuum oven at 45° C.for overnight to afford an amorphous form of(S)-3-((5-(3-morpholino-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)amino-5-phenyl-1,3-dihydro-2H-benzo[e][1,4]-diazepin-2-one/copovidone complex as a yellowish solid.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A process for preparing a compound of formula (I),

wherein {circle around (A)} is an optionally substituted aryl oroptionally substituted heteroaryl; each n is independently selected from1 and 2; m is 0, 1, 2, 3, or 4; and R₁ is selected from the groupconsisting of: 1) optionally substituted —C₁-C₈ alkyl; 2) optionallysubstituted —C₃-C₈ cycloalkyl; 3) optionally substituted 3- to12-membered heterocyclic; alternatively, two adjacent R₁ groups aretaken together with the carbon atoms to which they are attached to forma fused ring; two geminal R₁ groups are taken together with the carbonatom to which they are attached to form a spiro ring; or two R₁ groupson nonadjacent carbon atoms are taken together to form a bridging group,such as —CH₂— or —CH₂CH₂—; said process comprising the steps of: (a)reacting a compound of formula (VII),

wherein R₇ is selected from the group consisting of hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkenyl, 3- to 8-membered heterocyclic, aryl, and heteroaryl; and Xis a leaving group; with a compound of formula (VII-X),

wherein PG is hydrogen or an amine protecting group; to produce acompound of formula (VIII):

(b) reacting the compound of formula (VIII) with a compound of formula(IX):

to produce a compound of formula (X):

(c) reacting the compound of formula (X) with a compound of formula(III)

wherein R₅ is selected from the group consisting of —O(CO)O—R₆,optionally substituted aryl, and optionally substituted heteroaryl; andR₆ is selected from the group consisting of optionally substituted C₁-C₈alkyl, optionally substituted C₂-C₈ alkenyl, optionally substitutedC₂-C₈ alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted C₃-C₈ cycloalkenyl, optionally substituted 3- to 8 memberedheterocyclic, optionally substituted aryl, and optionally substitutedheteroaryl; to produce a compound of formula (V),

(d) reacting the compound of formula (V) with a cyclizing reagent toform the compound of formula (I).
 2. The process of claim 1, wherein


3. The process of claim 1, wherein step (a) is conducted in a proticsolvent at a temperature of about 10° C. to about 70° C.
 4. The processof claim 1, wherein R₇ is hydrogen, and step (a) is conducted in thepresence of an amide coupling agent.
 5. The process of claim 4, whereinthe amide coupling agent is HATU or EDU.
 6. The process of claim 4,wherein step (a) is conducted in a solvent selected from the groupconsisting of isopropyl acetate, ethyl acetate, dichloromethane,acetone, THF, NMP, 2-methyltetrahydrofuran, and acetonitrile.
 7. Theprocess of claim 1, wherein R₇ is C₁-C₈ alkyl, and step (a) is conductedin the presence of protic solvent.
 8. The process of claim 7, whereinthe protic solvent is methanol, ethanol, or isopropyl alcohol.
 9. Theprocess of claim 8, wherein step (a) is conducted at a temperature ofabout 10° C. to about 70° C. for about 3 to 12 hours.
 10. The process ofclaim 1, wherein step (b) is conducted (i) neat or (ii) in an aproticsolvent; at a temperature about 10° C. to about 100° C.
 11. The processof claim 1 further comprising the step of reacting compound (IV),

with a compound of the formula Y—C(O)R₅, wherein Y is a leaving group,to produce the compound of formula (III).
 12. The process of claim 11,wherein the compound of the formula Y—C(O)R₅ is 1,1′-carbonyldiimidazoleor nitrophenyl chloroformate.
 13. The process of claim 12, wherein thecompound of formula IV is reacted with the amine activating agent is asolvent selected from the group consisting of acetonitrile, THF, DMSO,and dichloromethane.
 14. The process of claim 1, wherein in step (c) isconducted in acetonitrile, THF, DMSO, DMF, sulfolane or1-methyl-2-pyrrolidone.
 15. The process of claim 14, wherein step (c) isconducted for 6 to 48 hours at a temperature of about 10 to 50° C. 16.The process of claim 1, wherein the cyclizing agent of step (d) ispara-toluenesulfonyl chloride.
 17. The process of claim 16, wherein step(d) is conducted (i) in the presence of triethylamine ordiisopropylethylamine; (ii) in a solvent selected from the groupconsisting of acetonitrile, THF, DMF, DMSO, NMP, acetone,dichloromethane, ethyl acetate and isopropyl acetate; (iii) at atemperature from about 0° C. to about 30° C., (iv) for about 3 to 15hours; (v) with a concentration of the compound of formula (III) ofabout 1 M to 3 M, and (vi) at a ratio of the concentration of thecompound of formula (III) and the concentration of the compound offormula (V) of about 1:1.
 18. The process of claim 1, wherein thecompound of formula I is compound I-a: